دورية أكاديمية
أعرض في EDS

AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.

التفاصيل البيبلوغرافية
العنوان: AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.
المؤلفون: Bone NB; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Becker EJ Jr; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Husain M; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Jiang S; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Zmijewska AA; Department of Nephrology, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Park DW; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Chacko B; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Darley-Usmar V; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Grégoire M; INSERM, EFS Bretagne, UMR U1236, Université Rennes, Rennes, France., Tadie JM; INSERM, EFS Bretagne, UMR U1236, Université Rennes, Rennes, France., Thannickal VJ; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA., Zmijewski JW; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA. zmijewsk@uab.edu.; Pulmonary, Allergy & Critical Care Medicine, School of Medicine, University of Alabama at Birmingham, 901 19th St. South, BMRII 406, Birmingham, AL, 35294, USA. zmijewsk@uab.edu.
المصدر: Scientific reports [Sci Rep] 2021 Jun 11; Vol. 11 (1), pp. 12387. Date of Electronic Publication: 2021 Jun 11.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Autophagy*, AMP-Activated Protein Kinases/*metabolism , Bacterial Infections/*immunology , Lung Diseases/*immunology , Sepsis/*immunology , Ubiquitin-Protein Ligases/*metabolism, Animals ; Humans ; Mice ; Mice, Inbred C57BL
مستخلص: Metabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2 -/- murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.
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معلومات مُعتمدة: P01 HL114470 United States HL NHLBI NIH HHS; R01 HL139617 United States HL NHLBI NIH HHS
المشرفين على المادة: EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 2.3.2.27 (parkin protein)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
تواريخ الأحداث: Date Created: 20210612 Date Completed: 20211028 Latest Revision: 20211028
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8196038
DOI: 10.1038/s41598-021-90573-0
PMID: 34117280
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-021-90573-0